Fueled by stem cells, skin epithelia self-renew throughout adult life. The long-term objectives of this research are to elucidate the genetic and molecular mechanisms that regulate skin development, homeostasis and regeneration, and to gain insights into how such control mechanisms go awry in skin diseases such as atopic dermatitis and cancer. Proper stem cell behaviors are key to the execution of normal regenerative programs and their misregulation underlies diseased conditions. Intricate control of gene expression sits at the very center of stem cell regulation, and for this reason we have focused our attention on transcriptional regulators. Past research in the laboratory supported by R01 AR047320 had presented Ovol transcription factors as excellent candidates for controlling the fate of skin epithelial stem and progenitor cells. Funding was discontinued at the last renewal, but exciting new data now poise us to probe into a previously under- appreciated territory of skin stem cell control. Surprisingly, both hair follicle and interfollicular epidermal stem/progenitor cells use Ovol factors to suppress their intrinsic tendency to undergo molecular and/or morphological changes that can ultimately lead to conversion into mesenchymal cell types (epithelial-to- mesenchymal transition or EMT) under permissive conditions. The tools and findings that we generated have laid a strong foundation for us to next ask how developmental progenitor cells and adult stem cells in the hair follicles balance their lineage plasticity with epithelial terminal differentiation to achieve normal morphogenesis and regeneration. Specifically, we ask the following questions in this application: 1) Is active suppression of EMT-like events essential for the morphogenesis and differentiation of embryonic hair follicle progenitor cells? 2) Do similar control mechanisms also operate in adult hair follicle stem cells during physiological hair regeneration? 3) Is the intrinsic EMT tendency of skin epithelial cells important for them to acquire expanded lineage potential during injury repair and how is this tendency kept in check to maintain epithelial differentiation? We will combine classical mouse genetics (conditional knockout and inducible overexpression) with modern techniques such as cell sorting, transcriptional profiling, lineage tracing, and ex vivo stem cell cultures to investiate the plasticity and differentiation of hair follicle stem/progenitor cells during morphogenesis and regeneration, under wild-type and mutant conditions.